It's surprising to report the listing status of "TiNi" in the disaster area!

Source: Pharmaceutical Economic News March 20, 2018 due to the CFDA review and approval system paying more and more attention to unmet clinical needs, the rare tide of approval of imported new drugs in recent years occurred in 2017 Among them, anti-tumor targeted oral medication is a more approved field of therapeutic drugs So, in the anti-tumor targeted oral medication, what is the situation of the listing of tyrosine kinase inhibitors and once serious "TiNi" drugs? Most of the newly marketed imported drugs are to fill the drug blank As shown in Table 1, non-small cell lung cancer (NSCLC), gastrointestinal stromal tumor, bone marrow fibrosis, chronic lymphocytic leukemia / small lymphocytic lymphoma, mantle cell lymphoma, melanoma and other treatment fields, all of which have targeted oral drug new products on the market Table 1: the original anti-tumor targeted oral drugs currently on the market Before that, there was no targeted oral drug for myelofibrosis, chronic lymphocytic leukemia / small lymphocytic lymphoma, mantle cell lymphoma and melanoma The marketing of lucotinib phosphate, ibotinib capsule and vimofinib made up for the current clinical drug blank The above three products have been included in the priority review list The current market of targeted oral drugs for NSCLC and gist will face competition from new products However, in the fields of chronic myeloid leukemia, advanced or metastatic breast cancer, advanced gastric cancer and liver cancer, only one targeted oral drug has been approved for domestic market   In addition, Xianda data v3.5 found that not all domestic anti-tumor targeted oral drugs have entered the list of drugs on the market in China Currently, there are eight products of imatinib mesylate capsule, imatinib mesylate tablet, sunitinib malate capsule, acitinib mesylate tablet, gefitinib tablet, exetinib hydrochloride tablet, oxitinib mesylate tablet and ibotinib capsule in the original research drug Enter the list of drugs listed in China It is not necessarily that all products listed in the Chinese drug catalog have instructions or review reports, such as sunitinib malate capsules Products with existing specifications or review reports will help domestic generic manufacturers to understand the information of the original drugs   Taking imatinib mesylate as an example, the indications included in the specification are: chronic, accelerated or acute phase of Philadelphia chromosome positive chronic myeloid leukemia (Ph + CML); adult patients with malignant gastrointestinal stromal tumor (GIST) who can not be resected and / or metastasized; children with Philadelphia chromosome positive acute lymphocytic leukemia (pH + all) who are newly diagnosed by combined chemotherapy Childhood patients; adult patients with recurrent or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + all) As well as indications of safety and effectiveness from foreign research data but limited data in Chinese population: eosinophilic syndrome (HES) and / or chronic eosinophilic leukemia (CEL) with fip1l1-pdgfr α fusion kinase; myelodysplastic syndrome / myeloproliferative disease (MDS / MPD) with platelet-derived growth factor receptor (PDGFR) gene Adult patients with rearrangement; adult patients with invasive systemic mastocytosis (ASM), without D816V c-kit gene mutation or unknown c-kit gene mutation; dermatofibrosarcoma protuberans (DFSP), which can not be resected, recurred or metastasized; adjuvant therapy for adult patients with significant recurrence risk after removal of kit (CD117) positive gist According to the instructions, we can know the efforts made by the original manufacturer of imatinib mesylate tablets in expanding the indications Only four anti-tumor targeted oral drugs have been approved for marketing in China, which were once declared overheated However, at present, there are only four approved generic products in China, namely imatinib mesylate capsules, imatinib mesylate tablets, dasatinib tablets and gefitinib tablets The above generic drugs were approved for marketing after 2013 The small number of domestic generic manufacturers may be related to the patent period According to the catalogue of drugs on the market in China, the expiry date of the indication patent of imatinib mesylate capsule and imatinib mesylate tablet is 2021, the expiry date of the product / composition patent of gefitinib tablet is 2023, the expiry date of the patent of ibotinib capsule is 2026, and the expiry date of the patent of the product / composition of oxitinib mesylate tablet is 2032 In addition, in March 2018, the acceptance number cyhs1790028 of dashatinib tablet of Ouyi Pharmaceutical Co., Ltd of Sinopharm group was announced not to be approved, which is predicted to be related to patent Imatinib mesylate capsule was launched in Zhengda Tianqing with an exclusive specification of 50mg, and imatinib mesylate tablets enjoyed an exclusive specification of 0.4g in the original research The usage and dosage of the instructions in the catalogue of drugs on the market in China are 0.4g or 0.6g for adults once a day, but the sales data of 50mg imatinib mesylate capsule and 0.4g imatinib mesylate tablet have not been monitored by the sample hospital The original research of Dasatinib Tablets has an exclusive specification of 100mg, and the initial dose of CML is 100mg However, only 20mg and 50mg are sold in the sample hospital at present, and the market share of 50mg is relatively large It can be seen that the current mainstream sales specifications on sale are not the lowest initial specifications for indications As shown in Table 2, the products listed in China before 2010, but no generic drugs have been listed, are sorafenib toluene sulfonate tablets, erlotinib hydrochloride tablets, sunitinib malate capsules and nilotinib capsules Among them, nilotinib capsule has not been started by any generic manufacturer Table 2 the current situation of domestic anti-tumor target drug generic drugs on the market and clinical start-up (data source: Xianda data v3.5) a few well-known domestic enterprises have achieved that Zhengda Tianqing is the domestic manufacturer with the largest number of anti-tumor target oral drug generic drugs on the market and products under research At present, Zhengda Tianqing has launched imatinib mesylate capsules and dasatinib tablets In addition to the two products mentioned above, there are also gefitinib tablets, sorafenib mesylate tablets, erlotinib hydrochloride tablets, sunitinib malate capsules, Everest tablets, lapatinib mesylate tablets, acitinib mesylate tablets and afatinib maleate tablets In addition to generic drugs, Zhengda Tianqing has also developed a new class 1 new drug, enrotinib hydrochloride capsule, which is targeted for oral use of anti-tumor drugs In April 2017, it won the priority review with "significant treatment advantages and major projects compared with existing treatment methods" In May 2017, it entered the list of the seventh batch of clinical self-examination and verification announcements, and in June 2017, it entered the announcement of drug clinical trial data on-site verification plan (No 12) The current registration status is "production site inspection" in December 2017, which is expected to be approved in the first half of 2018 The priority of generic drugs was also given to Zilu's gefitinib tablets and Shanghai chuano's erlotinib hydrochloride tablets Qilu pharmaceutical's gefitinib tablet was listed as the first generic in 2016 In 2016, Qilu pharmaceutical started the research of generic be only imatinib mesylate tablets Shanghai chuano erlotinib hydrochloride tablets are included in the priority review procedure for the reason of "drug production application one year before the expiration of patent" In April 2017, it entered the list of the Sixth Batch of self-examination clinical self-examination and verification announcements, and in October 2017, it entered the announcement of the on-site verification plan for drug clinical trial data (No 15) Currently, it is in the stage of information supplement After 2016, Shanghai chuano launched the generic be research, including gefitinib tablets and imatinib mesylate tablets Summary: since 2012, oral anti-tumor targeted drugs, especially tyrosine kinase inhibitors, have been reported as a serious treatment field in China However, from the current approved products and the policy trend of improving the requirements of the project by the reform of generic drug registration laws and regulations in 2015, we can see that the final products that can gain in this field are all domestic famous large factories for the time being There are three main restrictions: 1) although tyrosine kinase inhibitors are not hormones or cytotoxic drugs, GMP in most provinces They are required not to share the same line with other common preparations, or to have independent production lines; 2) at present, the registered batch requires the scale of 100000 tablets Although the market scale of tumor drugs is large, it is mainly due to the large unit price of products rather than large scale, and the cost of API is also very high, 100000 tablets are not affordable for all manufacturers; 3) there is independent development of research and development and production of anti-cancer drugs Li's manufacturers may be more favored when they are approved In conclusion, although tyrosine kinase inhibitors have been over declared, the final approval is expected to be mainly from large manufacturers In 2017, more new tyrosine kinase inhibitors were imported into the market, but the number of generic drugs approved was zero, and there may be a new breakthrough in 2018.